The role of the spreading depression (SD) was investigated in rats subjected to cardiac arrest cerebral ischemia (CACI). The SD was induced by application of KCl either on the exposed dura of the parietal cerebral cortex or by KCl perfusion through the hippocampus Three days later, the animals underwent the CACI. With regard to the hippocampus, unilateral perfusion with KCl regularly resulted in induction of SD in the ipsilateral hippocampus, associated with marked elevation of glutamate. No such effect was observed in rats in which KCl had been replaced with physiologic saline solution. Animals with hippocampal KCl perfusion, followed 3 days later by CACI, showed significant protection of CA1 pyramidal neurons on the side of the perfusion. No such effect was observed in Krebs-Ringer perfused rats. The protective effect of KCl on CA1 pyramidal neurons was evident also following the cortical application, although the effect was more bilateral. The SD induced 3 days before CACI resulted in a marked reduction in the susceptibility of rats to audiogenic seizures (AuSz) when tested 24 hr after cardiac arrest insult. To elucidate the protective nature of the SD, the brain tissue was studied in rats at various time intervals following induction of the SD and in various relevant control conditions. Our studies indicated a striking stimulation of protein synthesis in the hemisphere ipsilateral to SD, which was demonstrable only in animals with SD induction 3 days earlier. Elevation of protein synthesis was absent in rats sacrificed 1 or 7 days after SD induction and in all control groups of rats.